Faculty Bibliography

Previous studies have shown that central alpha1-adrenoceptor activity is necessary, acutely, for gross behavioral activity in response to novel surroundings and various psychostimulants. The present experiment tested whether it is also necessary for the hyperactivity produced by the peptide, orexin A, which is present in several central monoaminergic nuclei. Mice, pretreated intraventricularly with the alpha1-antagonist, terazosin, or the alpha2-antagonist, atipamezole, were given orexin A, intraventricularly (i.v.t.), and videotaped for gross movement and locomotion in the home cage between 30 and 60 min post-infusion. The alpha1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3 nmol dose and was near total at 30 nmol. The alpha2-antagonist, at 10 nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric alpha1-adrenoceptors, with 2,3-dichloro-alpha-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central alpha1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A

MRI may be used for detecting cartilage invasion in patients with laryngeal carcinoma. However, the normal laryngeal ossification pattern has not been studied. Our purpose was to examine the normal age-related signal patterns in the cricoid, thyroid and arytenoid cartilages on T1-weighted images. Signal in the cartilages was assessed by two radiologists in a blinded fashion using three-point scales for intensity and symmetry. Statistical analysis consisted of logistic and monotonic regression. There was excellent interobserver agreement (>85%) for all categories. The cartilages predominantly ossify symmetrically and the extent of high signal from all three increases with age. The latter may help in detection of cartilage invasion by tumor in older patients. Normal symmetry may be helpful when comparing sides for tumor invasion

The question of whether or not the locus coeruleus (LC) participates in the control of motor activity has been controversial due to difficulties in demonstrating permanent motor deficits after neurotoxic lesions of this nucleus or of the dorsal noradrenergic bundle (DNB). In the present experiments it was shown in rats that acute local blockade (with terazosin) or stimulation (with phenylephrine) of LC alpha(1)-adrenoceptors respectively blocked or stimulated exploratory behavior in a novel cage and the home cage. Moreover, previous lesion of the DNB by i.p. DSP4 abolished the behavioral changes to local LC alpha(1)-receptor manipulation but did not affect motor activity in the novel or home cage by itself. These findings are consistent with the hypothesis that the intact LC does contribute to motor activity control, exerted in part by its alpha(1)-receptors; however, the permanent loss of this nucleus is compensated for by remaining CNS motor structures

Brain alpha1-adrenoceptors that participate in behavioral activation were mapped in the mouse brain by determining where microinjection of the alpha1-antagonist, terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out of 23 tested regions were shown to be involved including the dorsal pons/locus coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on several of these regions simultaneously. A partial inhibition was obtained from the motor cortex. Coinjection of the alpha1/2-agonist, 6-fluoronorepinephrine (6FNE) but not the alpha2-agonist, dexmedetomidine (DMT) reversed the behavioral inhibition in all regions. It is hypothesized that brain motoric alpha1-receptors elicit behavioral activation by coordinately exciting several monoaminergic, motor and motivational systems

Brain alpha1-adrenoceptors have been shown to be essential for motor activity and movement in mice using intraventricular injection of alpha1-antagonists. To facilitate subsequent neuroanatomical mapping of these receptors, the present study was undertaken to replicate these effects in the rat. Rats were administered the alpha1-antagonist, terazosin, in the absence and presence of the alpha1-agonist, phenylephrine, in the IVth ventricle and were tested for their motor activity responses to an environmental change. Terazosin was found to produce a dose-dependent, virtually complete cessation of behavioral activity that was reversed by coinfusion of phenylephrine. The results could not be explained by sedation. It is concluded that central alpha1-adrenoceptors are essential for behavioral activation in rats as in mice

Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha(1B)-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain alpha(1)-adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI-alpha(1) system' may therefore represent a new target system for this disorder

A series of new findings on brain alpha1-adrenoceptors has confirmed and greatly extended the hypothesis that these receptors play a key role in depressive illness. First, in experiments using either the ivt. injection of the alpha1-antagonist, terazosin, and /or alpha1B-receptor deficient mice, it has been found that central alpha1 receptors are essential for spontaneous, novelty-and stimulant drug-induced behavioral activity. Second, these 'motoric' alpha1-receptors have also been shown to be present and to mediate neuronal excitation in 3 major monoamine-containing brain regions: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR) and nucleus accumbens as well as in the cerebellum which sends efferents to the LC, DR and ventral tegmental area. Third, the endogenous neurotransmitter at these motoric alpha1 receptors now appears to be EPI, based on studies of the marked immobility effects of PNMT inhibitors and their reversal by central EPI infusion. Fourth, a long-lasting depletion of brain EPI and a desensitization of brain alpha1-receptors involved in the potentiation of cAMP responses and the motor activating effect of the stimulant, modafinil has been found in stress models of depression in animals. And fifth, depressive illness may be associated with a marked 70-75% depletion of CSF EPI, which is reversed by antidepressant treatment, as well as a subsensitivity of central postsynaptic alpha1-receptors involved in the plasma cortisol response to amphetamine and desmethylimipramine. Based on these findings we postulate the existence of an EPI-innervated-alpha1-adrenergic system that regulates behavioral activation by costimulation of NE-, 5HT-and DAergic processes and is impaired both pre-and postsynaptically by stress and depressive illness

It has been shown that a subgroup of alpha1-adrenoceptors are both essential for spontaneous and novelty-induced behavioral activity and play a key role in the hyperactivity produced by stimulant drugs. In order to define which brain areas these motoric alpha1-receptors operate in, we have conducted a series of studies over the past 2 years on the ability of microinjections of the soluble alpha1-antagonist, terazosin, in various brain regions to induce immobility in a novel cage test. A total of 23 brain areas including those implicated in motor activation, circadian rhythm regulation, or having unusually high densities of alpha1-receptors were examined in mice. A total of 4 regions were found to show 'positive' responses to terazosin: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR), the nucleus accumbens (ACC) and the cerebellum. The IVth ventricle also yielded a strong immobility response probably due to combined action at the dorsal pons and cerebellum. Partial responses were obtained in the corpus striatum, anterior hypothalamus and medial preoptic region. No effect was found in the ventral tegmental area (VTA), substantia nigra, posterior hypothalamus, amygdala, BNST, prefrontal cortex or hippocampus. An increase in motor activity was found in the septum. The locations of these motoric alpha1-receptors in the dorsal pons, DR, ACC and possibly striatum suggests that they elicit behavioral activation by excitation of the 3 chief monoaminergic systems (NE, 5HT and DA)in the brain. In addition, the cerebellum is known to send efferents to the VTA, LC and DR. Other studies have suggested that motoric alpha1-adrenoceptors are innervated by brain epinephrine (EPI) and constitute a distinct neuronal system for coordinated behavioral activation

The role of brain epinephrine (EPI) in the regulation of motor activity and movement in mice was examined. Blockade of EPI synthesis with i.p. 2,3-dichloro-alpha-methylbenzylamine (DCMB) or LY134046 was found to produce marked behavioral inactivity which could be significantly reversed by intraventricular injection of EPI and by three other alpha(1)-adrenoceptor agonists, norepinephrine (NE), 6-fluoronorepinephrine (6FNE), and phenylephrine (PE), as well as by serotonin (5HT). EPI had the largest effect of these agonists and also was the only one that reversed nondrug-induced inactivity of mice in their home cages during the light phase. The effects of EPI were blocked by coinfusion of an alpha(1)-adrenoceptor antagonist (terazosin) but not of an alpha(2)-(atipamezole) or beta(1) (betaxolol)-blocker. The rank order of maximal behavioral responses to EPI, 6FNE, and PE in DCMB-treated mice was the same as the rank order of their maximal stimulation of hydrolysis of phosphatidylinositol at cloned alpha(1B)-adrenoceptors in cell culture. On the basis of the above findings and of the central distributions of adrenergic neurons and alpha(1)-adrenoceptors, the existence of a central EPI-innervated alpha(1)-adrenergic receptor system is postulated which serves to coexcite or enhance signaling in several monoaminergic brain regions involved in movement and motor activity